Abstract
Various angiogenic factors have been shown to play important roles in intraplaque angiogenesis, while little is known about the dynamic expression change and interplay between various angiogenic factors and intraplaque angiogenesis under high cholesterol conditions. New Zealand rabbits underwent balloon injury of the abdominal artery and then were assigned to a control group (n = 15, normal chow) or high cholesterol group (n = 25, 1% high cholesterol diet). At weeks 4, 6, 8, 10, and 12 after acclimation, rabbits (high cholesterol group, n = 5; control group, n = 3) were euthanized. No lesions were observed in the control group. From week 4 to week 12, the expression of vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR-2), fibroblast growth factor 2 (FGF-2), FGF receptor 1 (FGFR-1), platelet-derived growth factor-BB (PDGF-BB), and tumor necrosis factor alpha (TNF-α), the vulnerability index (VI) and the microvessel density (MVD) were significantly elevated in the high cholesterol group; however, PDGF receptor β (PDGFR-β) expression showed little change. Analysis by double-label immunofluorescence (CD31 and Ng2) and FITC-dextran indicated that the neovessels within the plaque were leaky due to a lack of pericytes. As indicated by Pearson’s correlation analysis, there was a highly positive correlation between the VI, MVD, macrophage content, and TNF-α level, and the levels of VEGF-A/VEGFR-2 and FGF-2/FGFR-1. However, no correlations were observed between PDGFR-β levels and the VI or MVD. High expression of VEGF-A/VEGFR-2 and FGF-2/FGFR-1 but not of PDGF-BB/PDGFR-β may contribute to immature and inflammatory intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis.
Highlights
Vulnerable atherosclerotic (AS) plaques are prone to rupture and are a major cause of acute coronary syndrome (ACS)
We found that, from week 4 to 12, the expression of vascular endothelial growth factor A (VEGF-A) and matrix metalloproteinases (MMPs), MMP-1, MMP-2, MMP-3, and MMP-9 increased with AS plaque development and that the expression of MMP-14 substantially decreased [4]
While there were no changes in serum lipid levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and TG during weeks 4, 6, 8, 10 or 12 in control rabbits (S1 Table), rabbits from the group that received a high cholesterol diet presented with severe hypercholesterolemia and exhibited a significant increase in the levels of the four serum proteins
Summary
Vulnerable atherosclerotic (AS) plaques are prone to rupture and are a major cause of acute coronary syndrome (ACS). VEGF-A/VEGFR-2 and FGF-2/FGFR-1 promotes intraplaque angiogenesis lipid cores containing an increased number of vasa vasorum and inflammatory cells and have been shown to cause frequent intraplaque hemorrhaging [1]. Plaques require extra nutrients in the blood supply, which is predominantly derived from intraplaque neovascularization [2]. Intraplaque angiogenesis refers to the process of new vessel formation within the plaque. Neovessels within the plaque are considered conduits of erythrocytes, lipid, and leukocytes into plaques, which contribute to the deterioration of interendothelial junctions, and intraplaque angiogenesis constitutes a strong indicator of rapid plaque progression and a possible contributing factor to the risk of rupture [3]
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